Bicalutamide, which is chemically known as N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methyl propanamide and represented by formula (I),
is a non-steroidal anti-androgen used in combination therapy with a Luteinizing Hormone Releasing Hormone (LHRH) analogue for treatment of advanced prostate cancer.
The first synthesis of Bicalutamide was disclosed by Tucker in U.S. Pat. No. 4,636,505, the key step essentially comprising oxidation of N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) thio]-2-hydroxy-2-methyl propanamide of formula (II),
to give Bicalutamide of formula (I). The sulfide compound is in turn prepared through reaction of 4-cyano-3-trifluoromethyl N-(2,3-epoxy-2methyl propionyl) aniline of formula (III)
with p-fluorothio phenol.
The synthesis of Bicalutamide as disclosed in U.S. Pat. No. 4,636,505 is summarized in Scheme-I
U.S. Pat. No. 4,636,505 mentions that the oxidizing agent and conditions used will determine whether a sulfinyl (S→O) or a sulfonyl (O═S═O) compound is obtained. Thus, oxidation with sodium metaperiodate in methanol solution at or below laboratory temperature was considered to convert a thio compound into the corresponding sulfinyl compound; and oxidation with a peroxy acid, for example m-chloroperbenzoic acid, in methylene chloride solution at or above laboratory temperature was considered to convert a thio compound into the corresponding sulfonyl compound. From the above as well as the description given in Example 6 of U.S. Pat. No. 4,636,505 it would be abundantly evident that the most preferred oxidizing agent is a peroxy acid, especially m-chloroperbenzoic acid.
A similar synthesis of Bicalutamide comprising oxidation of the sulfide (II) with m-chloroperbenzoic acid is disclosed by Tucker et al in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5 page 954-959.
Many variants/improvements of Bicalutamide synthesis have been subsequently reported, all of which in particular relate to certain improvements in the step of oxidation of sulfide (II) to Bicalutamide. These are:    i). Soros et al in WO 01/00608 A1, while stating that the method disclosed in U.S. Pat. No. 4,636,505 and Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5 page 954-959 is not industrially and environmentally safe provide an improved method comprising oxidation of the sulfide (II)            a) with an inorganic peroxy salt in a mixture of water and a solvent miscible or immiscible with water, in the latter case in the presence of a phase transfer catalyst, or        b) with aqueous hydrogen peroxide in presence of a C1-C4 aliphatic carboxylic acid, or under aqueous basic conditions, in presence of an organic solvent miscible with water, or in an organic solvent immiscible with water in the presence of a phase transfer catalyst and a salt of a metal belonging to the vanadium or chromium group.            ii). Chen, Bang-Chi et al in WO 02/24638 A1 also disclose oxidation of sulfide (II) using conventional oxidizing agents known in the art, specifically a peroxy acid, such as peracetic acid, trifluoroperacetic acid, 3-chloroperbenzoic acid, and the like; dioxiranes such as dimethyldioxirane, methyltrifluoromethyldioxirane, and the like; hydrogen peroxide; sodium periodate; N-methylmorpholine; N-oxide and Oxone, with peroxy acids in particular trifluoroacetic acid being more preferable. The specification further states that trifluoroperacetic acid is preferably formed in situ from hydrogen peroxide and trifluoroacetic anhydride. Typically the oxidation is carried out by treating a solution of sulfide (II) in dichloromethane with 30% aqueous hydrogen peroxide solution and cooling the mixture to −55° C., followed by addition of trifluoroacetic anhydride and allowing the oxidation to proceed at a temperature of between −15° C. to 0° C.    iii). Tetsuya et al in U.S. Pat. No. 6,740,770 have criticized the method disclosed by Tucker et al in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5 page 954-959 as well as U.S. Pat. No. 4,636,505 in that they utilize dichloromethane as a solvent in the oxidation step, which is harmful, potentially carcinogenic, expensive and creates a burden in waste treatment. U.S. Pat. No. 6,740,770 further criticizes the method disclosed by Tucker et al in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 5 page 954-959 as using m-chloroperbenzoic acid as an oxidizing agent, which is not only highly explosive but also expensive and possess an economic problem.            Furthermore, U.S. Pat. No. 6,740,770 criticizes the methods disclosed by WO 01/00608 A1 and WO 02/24638 A1 as also not industrially and environmentally benign as well as not safe and expensive in that the said methods are found to utilize again dichloromethane in one of the steps, utilize cryogenic temperature of −55° C., utilize expensive trifluoroacetic anhydride as a reactant.        Accordingly, U.S. Pat. No. 6,740,770 provides an alternate method, which is reportedly an economically and industrially viable method for production of Bicalutamide, the key feature of which comprises oxidation of sulfide (II) with:        a) Aqueous hydrogen peroxide (H2O2) in ethyl acetate as solvent and in presence of sodium tungstate or a solvate there of, phenylphosphonic acid and a phase transfer catalyst; or        b) Monoperpthalic acid prepared from pthalic anhydride and hydrogen peroxide.        When aqueous hydrogen peroxide is employed as oxidizing agent, the oxidation reaction requires that it be carried out in the presence of sodium tungstate, phenyl phosphonic acid and phase transfer catalyst with at least up to 20 fold excess of hydrogen peroxide employed. Use of such large excess of hydrogen peroxide makes the process not particularly safe. Furthermore, use of sodium tungstate, its hydrates and its solvates as well as expensive phase transfer catalysts such as tetrabutylammonium bromide, benzyl trimethylammonium chloride, tetrabutylammonium hydroxide and the like make the method specially not economical.        In the case of oxidation using Monoperpthalic acid apart from the hazards associated with its use, low temperatures of between 0 to −30° C. are recommended, thereby increasing the cost of manufacture.            iv). Shintaku, Tetsuya et al in WO2005/037777 disclose an oxidation reaction with per carboxylic acid, which again is associated with the shortcomings mentioned hereinbefore.From the foregoing, it would be apparent that the reported methods for synthesis of Bicalutamide suffer from one or more of the following limitations, viz.    a) Use of halogenated solvents specially dichloromethane, which is harmful, potentially carcinogenic, expensive and creates a burden in waste treatment;    b) Use of peroxy acids such as m-chloroperbenzoic acid, hydrogen peroxide, trifluoroperacetic acid Monoperpthalic acid as oxidizing agents, which are highly explosive in nature thereby causing safety and environment concerns;    c) Use of cryogenic temperature as low as −50° C. or higher temperatures of about 80° C., which requires energy and thereby increasing the cost of manufacturing;    d) Use of expensive tungsten, vanadium or chromium compounds which are not only expensive but also create problem in waste disposal; and    e) Use of corrosive chemicals like trifluoroacetic anhydride, which calls for extreme precautions not only in handling as well as create problems in waste disposal.
Further, the by-products of such oxidation reactions e.g. benzoic acid obtained on oxidation when m-chloroperbenzoic acid are also in many instances difficult to remove calling for tedious separation and purification techniques.
Considering the therapeutic and commercial importance of Bicalutamide there exists a need for a method which is free of the limitations of the prior art methods and which, more over is safe, simple convenient and economical.
The present invention is a step forward in this direction and provides a simple convenient and economical method for manufacture of Bicalutamide, which is both industrially and environmentally safe.